Denise L Faustman

Harvard Medical School, Boston, Massachusetts, United States

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Publications (88)664.91 Total impact

  • Toshiyuki Mera, Denise L Faustman
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    ABSTRACT: Papain is a protease with potential use in transplantation because of its targeted capacity to selectively remove human leukocyte antigen (HLA) class I proteins from donor human cells. However, its proteolytic activity has not been studied under conditions suitable for use in perfusing donor organs, namely, under a temperature of 4°C and dissolution in Belzer-UW solution.
    Transplantation 10/2014; · 3.78 Impact Factor
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    ABSTRACT: Non-obese diabetic mice (NOD) exhibit autoimmune Sjögren-like disease (SS-like). We reported previously that a combined-therapy consisting of immuno- and cell-based therapy rescued NOD from SS-like. However, therapies tested to date on NOD mice were aimed at the initial phase of SS-like. It is unknown whether therapies are effective in restoring salivary function when given at an advanced phase of SS-like. The efficacy of two therapies (bone marrow versus spleen cells) was compared head-to-head for halting/reversing salivary hypofunction at two critical time points of SS-like (7-week-old NOD with normal saliva output and 20-week-old NOD with minimal saliva). NOD mice were divided into four groups: (i) control, (ii) complete Freund's adjuvant (CFA), (iii) bone marrow transplants with CFA or (iv) spleen cell transplants with CFA. Mice were monitored 8-12 months after therapy. Both cell therapies were effective during the initial phase of SS-like; salivary flow rates were maintained between 80-100% of pre-symptomatic levels. Spleen cell therapy was better than bone marrow when administered in the initial phase of SS-like. When cell therapies were given at an advanced phase of SS-like (20 weeks and older), salivary flow rates improved but were at best 50% of pre-symptomatic levels. Both cell therapies decreased tumor necrosis factor-α, transforming growth factor-β1 levels and T and B cells while increasing epidermal growth factor and regulatory T cells. Elevated serum epidermal growth factor levels were measured in spleen-treated mice. A therapeutic effect in advanced phase disease, albeit in mice, holds promise for humans in which Sjögren syndrome is generally not diagnosed until a late stage.
    Cytotherapy 01/2014; · 3.06 Impact Factor
  • Denise L Faustman
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    ABSTRACT: The type 1 diabetes field has held firm to the dogma that the pancreas is no longer viable, and thus incapable of producing insulin, within 1 to 2 years of diagnosis for the majority of patients. A new study in this issue of Diabetologia (DOI: 10.1007/s00125-013-3067-x ), based on a hypersensitive assay, has found detectable C-peptide, a marker of insulin production, in individuals with long-standing type 1 diabetes. This new study confirms and expands a decades-long track record of research finding intact pancreatic islet cells in advanced disease. Because the evidence, stemming back to 1902, was largely histological in nature, it was dismissed as lacking functional corroboration. This new study in patients with long-term diabetes shows appropriate functioning of pancreatic islet cells after exposure to a mixed-meal stimulus. The weight of evidence now makes it clear that a large fraction of patients with long-standing diabetes have low level, but persistent functioning of pancreatic islet cells enduring more than a decade after disease onset.
    Diabetologia 11/2013; · 6.49 Impact Factor
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    ABSTRACT: Sjogren's syndrome (SS) is a complex autoimmune disease that primarily affects salivary and lacrimal glands and is associated with high morbidity. Although the prevailing dogma is that immune system pathology drives SS, increasing evidence points to structural defects, including defective E-cadherin adhesion, to be involved in its etiology. We have shown that E-cadherin has pivotal roles in the development of the mouse salivary submandibular gland (SMG) by organizing apical-basal polarity in acinar and ductal progenitors and by signaling survival for differentiating duct cells. Recently, E-cadherin junctions have been shown to interact with effectors of the Hippo signaling pathway, a core pathway regulating the organ size, cell proliferation, and differentiation. We now show that Hippo signaling is required for SMG-branching morphogenesis and is involved in the pathophysiology of SS. During SMG development, a Hippo pathway effector, TAZ, becomes increasingly phosphorylated and associated with E-cadherin and α-catenin, consistent with the activation of Hippo signaling. Inhibition of Lats2, an upstream kinase that promotes TAZ phosphorylation, results in dysmorphogenesis of the SMG and impaired duct formation. SMGs from non-obese diabetic mice, a mouse model for SS, phenocopy the Lats2-inhibited SMGs and exhibit a reduction in E-cadherin junctional components, including TAZ. Importantly, labial specimens from human SS patients display mislocalization of TAZ from junctional regions to the nucleus, coincident with accumulation of extracellular matrix components, fibronectin and connective tissue growth factor, known downstream targets of TAZ. Our studies show that Hippo signaling has a crucial role in SMG-branching morphogenesis and provide evidence that defects in this pathway are associated with SS in humans.Laboratory Investigation advance online publication, 30 September 2013; doi:10.1038/labinvest.2013.114.
    Laboratory Investigation 09/2013; · 3.96 Impact Factor
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    Denise L Faustman
    Expert Review of Clinical Immunology 02/2013; 9(2):95-7. · 2.89 Impact Factor
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    ABSTRACT: T-regulatory cells (Tregs) are a rare lymphocyte subtype that shows promise for treating infectious disease, allergy, graft-versus-host disease, autoimmunity, and asthma. Clinical applications of Tregs have not been fully realized because standard methods of expansion ex vivo produce heterogeneous progeny consisting of mixed populations of CD4 + T cells. Heterogeneous progeny are risky for human clinical trials and face significant regulatory hurdles. With the goal of producing homogeneous Tregs, we developed a novel expansion protocol targeting tumor necrosis factor receptors (TNFR) on Tregs. In in vitro studies, a TNFR2 agonist was found superior to standard methods in proliferating human Tregs into a phenotypically homogeneous population consisting of 14 cell surface markers. The TNFR2 agonist-expanded Tregs also were functionally superior in suppressing a key Treg target cell, cytotoxic T-lymphocytes. Targeting the TNFR2 receptor during ex vivo expansion is a new means for producing homogeneous and potent human Tregs for clinical opportunities.
    Scientific Reports 01/2013; 3:3153. · 5.08 Impact Factor
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    Denise L Faustman, Miriam Davis
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    ABSTRACT: THE REGULATORY CYTOKINE TUMOR NECROSIS FACTOR (TNF) EXERTS ITS EFFECTS THROUGH TWO RECEPTORS: TNFR1 and TNFR2. Defects in TNFR2 signaling are evident in a variety of autoimmune diseases. One new treatment strategy for autoimmune disease is selective destruction of autoreactive T cells by administration of TNF, TNF inducers, or TNFR2 agonism. A related strategy is to rely on TNFR2 agonism to induce T-regulatory cells (Tregs) that suppress cytotoxic T cells. Targeting TNFR2 as a treatment strategy is likely superior to TNFR1 because of its more limited cellular distribution on T cells, subsets of neurons, and a few other cell types, whereas TNFR1 is expressed throughout the body. This review focuses on TNFR2 expression, structure, and signaling; TNFR2 signaling in autoimmune disease; treatment strategies targeting TNFR2 in autoimmunity; and the potential for TNFR2 to facilitate end organ regeneration.
    Frontiers in Immunology 01/2013; 4:478.
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    Limei Wang, Nicholas Fraser Lovejoy, Denise L Faustman
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    ABSTRACT: To examine persistence of C-peptide production by ultrasensitive assay years after onset of type 1 diabetes and factors associated with preserving β-cell function. Serum C-peptide levels, a marker of insulin production and surviving β-cells, were measured in human subjects (n = 182) by ultrasensitive assay, as was β-cell functioning. Twenty-two times more sensitive than standard assays, this assay's lower detection limit is 1.5 pmol/L. Disease duration, age at onset, age, sex, and autoantibody titers were analyzed by regression analysis to determine their relationship to C-peptide production. Another group of four patients was serially studied for up to 20 weeks to examine C-peptide levels and functioning. The ultrasensitive assay detected C-peptide in 10% of individuals 31-40 years after disease onset and with percentages higher at shorter duration. Levels as low as 2.8 ± 1.1 pmol/L responded to hyperglycemia with increased C-peptide production, indicating residual β-cell functioning. Several other analyses showed that β-cells, whose C-peptide production was formerly undetectable, were capable of functioning. Multivariate analysis found disease duration (β = -2.721; P = 0.005) and level of zinc transporter 8 autoantibodies (β = 0.127; P = 0.015) significantly associated with C-peptide production. Unexpectedly, onset at >40 years of age was associated with low C-peptide production, despite short disease duration. The ultrasensitive assay revealed that C-peptide production persists for decades after disease onset and remains functionally responsive. These findings suggest that patients with advanced disease, whose β-cell function was thought to have long ceased, may benefit from interventions to preserve β-cell function or to prevent complications.
    Diabetes care 03/2012; 35(3):465-70. · 7.74 Impact Factor
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    ABSTRACT: No targeted immunotherapies reverse type 1 diabetes in humans. However, in a rodent model of type 1 diabetes, Bacillus Calmette-Guerin (BCG) reverses disease by restoring insulin secretion. Specifically, it stimulates innate immunity by inducing the host to produce tumor necrosis factor (TNF), which, in turn, kills disease-causing autoimmune cells and restores pancreatic beta-cell function through regeneration. Translating these findings to humans, we administered BCG, a generic vaccine, in a proof-of-principle, double-blind, placebo-controlled trial of adults with long-term type 1 diabetes (mean: 15.3 years) at one clinical center in North America. Six subjects were randomly assigned to BCG or placebo and compared to self, healthy paired controls (n = 6) or reference subjects with (n = 57) or without (n = 16) type 1 diabetes, depending upon the outcome measure. We monitored weekly blood samples for 20 weeks for insulin-autoreactive T cells, regulatory T cells (Tregs), glutamic acid decarboxylase (GAD) and other autoantibodies, and C-peptide, a marker of insulin secretion. BCG-treated patients and one placebo-treated patient who, after enrollment, unexpectedly developed acute Epstein-Barr virus infection, a known TNF inducer, exclusively showed increases in dead insulin-autoreactive T cells and induction of Tregs. C-peptide levels (pmol/L) significantly rose transiently in two BCG-treated subjects (means: 3.49 pmol/L [95% CI 2.95-3.8], 2.57 [95% CI 1.65-3.49]) and the EBV-infected subject (3.16 [95% CI 2.54-3.69]) vs.1.65 [95% CI 1.55-3.2] in reference diabetic subjects. BCG-treated subjects each had more than 50% of their C-peptide values above the 95(th) percentile of the reference subjects. The EBV-infected subject had 18% of C-peptide values above this level. We conclude that BCG treatment or EBV infection transiently modified the autoimmunity that underlies type 1 diabetes by stimulating the host innate immune response. This suggests that BCG or other stimulators of host innate immunity may have value in the treatment of long-term diabetes. ClinicalTrials.gov NCT00607230.
    PLoS ONE 01/2012; 7(8):e41756. · 3.53 Impact Factor
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    ABSTRACT: Progress in clinical trials in infectious disease, autoimmunity, and cancer is stymied by a dearth of successful whole cell biomarkers for peripheral blood lymphocytes (PBLs). Successful biomarkers could help to track drug effects at early time points in clinical trials to prevent costly trial failures late in development. One major obstacle is the inaccuracy of Ficoll density centrifugation, the decades-old method of separating PBLs from the abundant red blood cells (RBCs) of fresh blood samples. To replace the Ficoll method, we developed and studied a novel blood-based magnetic separation method. The magnetic method strikingly surpassed Ficoll in viability, purity and yield of PBLs. To reduce labor, we developed an automated platform and compared two magnet configurations for cell separations. These more accurate and labor-saving magnet configurations allowed the lymphocytes to be tested in bioassays for rare antigen-specific T cells. The automated method succeeded at identifying 79% of patients with the rare PBLs of interest as compared with Ficoll's uniform failure. We validated improved upfront blood processing and show accurate detection of rare antigen-specific lymphocytes. Improving, automating and standardizing lymphocyte detections from whole blood may facilitate development of new cell-based biomarkers for human diseases. Improved upfront blood processes may lead to broad improvements in monitoring early trial outcome measurements in human clinical trials.
    PLoS ONE 01/2011; 6(7):e22430. · 3.53 Impact Factor
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    Denise L Faustman, Miriam Davis
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    ABSTRACT: The view of the spleen as an unnecessary organ has been shattered. The evidence shows the spleen to be a source of naturally-occurring multipotent stem cells with possibly pluripotent potential. The stem cells are sequestered in the spleen of not only of animals but also of normal human adults. The reservoir of cells is set for differentiation and they need not be manipulated in vitro or ex vivo before autologous or heterologous use. Splenic stem cells, of Hox11 lineage, have been found in disease or injury to differentiate into pancreatic islets, salivary epithelial cells and osteoblast-like cells, cranial neurons, cochlea, lymphocytes, and more differentiated immune cells that repair injured heart cells. Injury or disease in target tissues induces these stem cells, still in the spleen, to upregulate the same embryonic transcription factors artificially introduced into induced pluripotent stem cells (iPS). Splenic stem cells may have broad pluripotent potential, but unlike iPS cells, possess low oncogenic risk.
    The international journal of biochemistry & cell biology 10/2010; 42(10):1576-9. · 4.89 Impact Factor
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    Denise Faustman, Miriam Davis
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    ABSTRACT: Although drug development has advanced for autoimmune diseases, many current therapies are hampered by adverse effects and the frequent destruction or inactivation of healthy cells in addition to pathological cells. Targeted autoimmune therapies capable of eradicating the rare autoreactive immune cells that are responsible for the attack on the body's own cells are yet to be identified. This Review presents a new emerging approach aimed at selectively destroying autoreactive immune cells by specific activation of tumour necrosis factor receptor 2 (TNFR2), which is found on autoreactive and normal T lymphocytes, with the potential of avoiding or reducing the toxicity observed with existing therapies.
    dressNature Reviews Drug Discovery 06/2010; 9(6):482-93. · 33.08 Impact Factor
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    ABSTRACT: The adult spleen harbors a population of naturally occurring multipotent stem cells of non-lymphoid lineage (CD45-). In animal models, these splenic stem cells can directly or indirectly contribute to regeneration of bone, inner ear, cranial nerves, islets, hearts and salivary glands. Here we characterize the CD45- stem cell proteome to determine its potential broader multipotency versus its protection from malignant transformation. Using state-of-the-art proteomics and in vivo testing, we performed functional analyses of unique proteins of CD45- (non-lymphoid) splenic stem cells, as compared with CD45+ (lymphoid) cells. CD45- stem cell-specific proteins were identical to those in iPS, including OCT3/4, SOX2, KLF4, c-MYC and NANOG. They also expressed Hox11, Gli3, Wnt2, and Adam12, the benchmark transcription factors of embryonic stem cells. These transcription factors were functional because their mRNA was upregulated in the spleen in association with ongoing damage to the pancreas and salivary glands, organs to which they normally contribute stem cells. We also show low likelihood of malignant transformation. Our proteomic and functional analyses reveals that naturally occurring CD45- stem cells of the spleen are the first-ever candidates for naturally occurring population of embryonic and iPS cells with low oncogenic risk. Given their presence in normal humans and mice, splenic stem cells are poised for translational research.
    The international journal of biochemistry & cell biology 12/2009; 42(10):1651-60. · 4.89 Impact Factor
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    Denise L Faustman, Miriam Davis
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    ABSTRACT: Type I diabetes (TID) is an autoimmune disease in which insulin-secreting beta cells of the pancreatic islets are destroyed by T lymphocytes. Until the 1990s, the prevailing dogma was that the attack was attributable to rogue T lymphocytes bearing CD4 markers on their surface (CD4 T helper lymphocytes). Today, the prevailing view is that rogue T cells bearing CD8 markers or cytotoxic CD8 T lymphocytes are also important and perhaps the foremost contributors to beta-cell death. Recognizing CD8 T-cell subsets as the prime culprits has helped to trace the disease's pathogenesis to abnormal T-cell education. Defective education can occur when antigen-presenting cells fail to assemble and present self-antigens to naïve T cells. The failure in that process, normally designed to prevent T cells' attack on the body's own antigens, enables self-reactive T cells to escape into the circulation. Once released, the self-reactive CD8 T cells kill specific self-antigens, which, in the case of TID, include insulin and other key proteins associated with beta cell functions. Abnormalities during T-cell education have been mapped in part to genetic defects in specific gene-encoding regions of the major histocompatibility complex class I region and to proteins that assemble self-peptides into the MHC class I structure that map within the MHC class II region. Two decades of research have led to understanding of genetic and functional defects in the immune system, placing us at the threshold of finding new therapeutic strategies aimed at eliminating autoreactive CD8 T cells, while preserving healthy immune cells.
    Journal of Molecular Medicine 09/2009; 87(12):1173-8. · 4.77 Impact Factor
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    Denise L Faustman
    New England Journal of Medicine 11/2008; 359(18):1956-8. · 54.42 Impact Factor
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    ABSTRACT: Human autoimmune (AI) diseases are difficult to treat, because immunosuppressive drugs are nonspecific, produce high levels of adverse effects, and are not based on mechanistic understanding of disease. Destroying the rare autoreactive T lymphocytes causing AI diseases would improve treatment. In animal models, TNF selectively kills autoreactive T cells, thereby hampering disease onset or progression. Here, we seek to determine, in fresh human blood, whether TNF or agonists of TNF selectively kill autoreactive T cells, while sparing normal T cells. We isolated highly pure CD4 or CD8 T cells from patients with type 1 diabetes (n = 675), other AI diseases, and healthy controls (n = 512). Using two cell death assays, we found that a subpopulation of CD8, but not CD4, T cells in patients' blood was vulnerable to TNF or TNF agonist-induced death. One agonist for the TNFR2 receptor exhibited a dose-response pattern of killing. In type 1 diabetes, the subpopulation of T cells susceptible to TNF or TNFR2 agonist-induced death was traced specifically to autoreactive T cells to insulin, a known autoantigen. Other activated and memory T cell populations were resistant to TNF-triggered death. This study shows that autoreactive T cells, although rare, can be selectively destroyed in isolated human blood. TNF and a TNFR2 agonist may offer highly targeted therapies, with the latter likely to be less systemically toxic.
    Proceedings of the National Academy of Sciences 10/2008; 105(36):13644-9. · 9.81 Impact Factor
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    A Lonyai, S Kodama, D Burger, M Davis, D L Faustman
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    ABSTRACT: The spleen of human adults uniquely possesses a reservoir of multilineage adult stem cells that express the developmental transcription factor HOX11. In contrast to hematopoietic stem cells, HOX11+ stem cells hold potentially broader therapeutic applications because they are less lineage restricted. HOX11/TLX1 is part of a homeodomain gene family essential for organogenesis of the spleen and for contributions to development of hindbrain, cochlea, pancreas, salivary glands, among other organs and tissues. While HOX11/TLX1 displays widespread patterns of expression during embryogenesis, its expression was thought to cease after birth. Recent findings in human post-mortem tissue have shattered this dogma, finding that HOX11/TLX1 stem cells are uniquely and abundantly expressed throughout adulthood in the human spleen. While their role in humans is not yet understood, HOX11/TLX1 stem cells from the spleen of normal mice have been harvested to assist in both the treatment and cure at least two autoimmune diseases: type 1 diabetes, Sjogren's syndrome, and possibly their comorbid hearing loss. The splenic stem cells are infused, with an immune therapy, into diseased NOD mice, where they can home to the diseased organ, differentiate into the appropriate cell type, and assume normal functioning with the endogenous regeneration of the animal due to disease removal. This review covers HOX11/TLX1+ stem cells' success in an animal model and their potential for treating autoimmune diseases in organs that mirror their extensive expression patterns during embryogenesis.
    Hormone and Metabolic Research 03/2008; 40(2):137-46. · 2.15 Impact Factor
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    ABSTRACT: Developmental biology has long been ignored in the etiology and diverse manifestations of autoimmune diseases. Yet a role for development is suggested by intriguing overlaps in particular organs targeted in autoimmune diseases, in this case type 1 diabetes and Sjogren's syndrome. Patients with type 1 diabetes have high rates of co-occurring Sjogren's syndrome, and both conditions are associated with hearing loss and tongue abnormalities. All of these co-occurrences are found in organs tracing their lineage to the developmental transcription factor Hox11, which is expressed in embryonic cells destined for the pancreas, salivary glands, tongue, cranial nerves and cochlea. To determine whether development contributes to autoimmunity, we compared four target organs in NOD mice (an animal model for type 1 diabetes and Sjogren's syndrome) with NOD-SCID mice (which lack lymphocytes) and normal controls. We examined the structure and/or function of the cochlea, salivary glands, pancreas and tongue at early time points after birth. Before the usual time of the onset of type 1 diabetes or Sjogren's syndrome, we show that all four Hox11-derived organs are structurally abnormal in both NOD mice and NOD-SCID mice versus controls. The most striking functional defect is near complete hearing loss occurring before the normal time of the onset of autoimmunity. The hearing loss is associated with severe structural defects in the cochlea, suggesting that near-deafness occurs independent of autoimmune attack. The pancreas and salivary glands are also structurally abnormal in NOD and NOD-SCID mice, but they are functionally normal. This suggests that autoimmune attack of these two organs is required for functional failure. We conclude that a developmental lineage of cells contributes to autoimmunity and predicts which organs may be targeted, either structurally and/or functionally. Taken together, our findings challenge the orthodoxy that autoimmunity is solely caused by a defective immune system.
    Immunology and Cell Biology 02/2008; 86(4):301-9. · 3.93 Impact Factor
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    Leukemia 11/2007; 21(10):2192-4. · 10.16 Impact Factor
  • Denise L Faustman
    Science 08/2007; 317(5835):196. · 31.20 Impact Factor

Publication Stats

1k Citations
664.91 Total Impact Points

Institutions

  • 1996–2014
    • Harvard Medical School
      • Department of Cell Biology
      Boston, Massachusetts, United States
  • 1990–2013
    • Massachusetts General Hospital
      • • Immunobiology Laboratory
      • • Department of Medicine
      • • Diabetes Unit
      Boston, Massachusetts, United States
  • 2009–2010
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1995–2001
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, Massachusetts, United States
  • 1989
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States